Stored blood undergoes a number of deleterious biochemical changes over time, known collectively as xe2x80x9cstorage lesion.xe2x80x9d These changes can include microaggregation of cells, hemolysis, vesicle formation, decreased membrane flexibility, decreased stability, and increased hemoglobin-oxygen affinity. The changes reduce the overall benefit of administering stored blood or red blood cell containing blood products to the patient and may even cause deleterious effects when transfused into a patient. For example, increased microaggregate formation and loss of membrane flexibility of the red blood cells may cause blockage of microcirculatory vessels resulting in local ischemia and pulmonary dysfunction.
Additionally, the loss of 2,3-diphosphoglycerate (2,3-DPG) in red blood cells results in substantially increased hemoglobin-O2 affinity. Blood stored for greater than one week shows a significant decrease in 2,3-DPG levels. After two weeks, only about 40% of 2,3-DPG remains and by three weeks only about 10% remains. (S. P. Masouredis, Preservation and Clinical Use of Erythrocytes and Whole Blood, Chapter 164, In: Hemology, 3rd edition, Williams, Beutler, Erslev and Lichtman, (eds.) McGraw-Hill, NY, pp. 1529-1549 (1983)). The loss of 2,3-DPG produces a concomitant drop in P50. For example, after four weeks of storage in the preservative, citrate phosphate dextrose (CPD), the P50 of packed red cells drops to approximately 15 mm Hg (Wells et al., Transfusion 21:709-714 (1981)). Since release of oxygen from red blood cells usually is proportional to P50, the capacity of stored red blood cells to deliver oxygen also decreases over time.
Storage lesions can cause deleterious changes in oxygen transport by decreasing both convective and diffusive oxygen delivery. Microaggregates and inflexible cells may be caught in microvessels, blocking flow to downstream tissue. Additionally, red blood cells containing hemoglobin with relatively high oxygen affinity have reduced ability to release oxygen to tissue. Stored red blood cells having high affinity for oxygen can xe2x80x9crejuvenatexe2x80x9d over time after transfusion into the body. Levels of 2,3-DPG return to 30% to 50% of normal by four hours and to normal levels with approximately twenty-four hours, though this rate can be variable. (Valeri and Hirsch, J. Lab. Clin. Med. 73:722-733 (1969); Beutler and Wood, J. Lab. Clin. Med. 74:300-304 (1969)). The rate of 2,3-DPG recovery may be dependent upon the metabolic state of the patient. (O""Brien and Watkins, J. Thor. and Cardiovas. Surg. 40:611 (1960)). Ironically, stored red blood cells are transfused to meet an acute need, but suffer from acute lesion.
While these cells xe2x80x9crejuvenatexe2x80x9d in circulation, regaining flexibility and decreasing oxygen affinity over a period of hours, there is a window of reduced oxygen transport that could adversely affect patients, especially those patients that are critically ill. Furthermore, while young healthy patients may compensate for storage lesion; patients with reduced or absent ability to compensate are put at risk of further injury or reduced efficacy of treatment. Paradoxically, this compensatory response of transfusion of red blood cells having high affinity for oxygen in some cases may cause decreased local oxygenation. (Marik and Sibbald, JAMA 269:3024-30 (1993)). Production of microemboli is also part of the storage lesion. Microemboli are known to form in packed red cells during storage and on infusion obstruct the microcirculation, causing damage to pulmonary capillary endothelium and alveolar epithelium (Liu, et al., Ann. Thorac. Surg. 54:1196-1202 (1992); Gay, et al., Trauma 19:80-84 (1979)).
Fresh red blood cells have been recommended for massive transfusions, transfusions of infants, older patients, and patients with cardiovascular and pulmonary disease (Masouredis, S. P., Preservation and Clinical Use of Blood and Blood Components,xe2x80x9d In: Hemology, (Williams, W. J., Beutler, E., Erslev, A. J. and Lichtman, M. A. eds.) McGraw-Hill, New York, pp. 1529-1549; Sugarman, H. J., et al. Surg. Gynecol. Obstet., 131:733-741 (1970); Valeri, G. R., et al., Transfusion 20:263-276 (1980); Hess, W., Anaesthetist., 36:455-467 (1987)). However, the availability of fresh blood cells often is limited.
Therefore, a need exists for products and methods that improve the oxygen transport and delivery efficiency of stored red blood cells.
The present invention is drawn to a method of treating a patient, by administering to the patient stored red blood cells and a hemoglobin solution.
In one embodiment the hemoglobin solution is administered to the patient, and thereafter stored red blood cells are administered, wherein the hemoglobin solution comprises polymerized hemoglobin and wherein the stored red blood cells have been stored for greater than about forty-eight hours.
In another embodiment, the method includes administering stored red blood cells to the patient and thereafter administering a hemoglobin solution within about eight hours of administering the stored red blood cells, wherein the hemoglobin solution comprises polymerized hemoglobin and wherein the stored red blood cells have been stored for greater than about forty-eight hours.
The present invention is further drawn to a composition comprising a hemoglobin solution and stored red blood cells, wherein the stored red blood cells have been stored for greater than about forty-eight hours.
As demonstrated herein, although storage of red blood cells over time reduced the rate of oxygen release from red blood cells, administration of a hemoglobin solution in addition to stored red blood cells reversed this effect and restored oxygen delivery potential to stored red blood cells. The resulting mixture behaved more like fresh red blood cells in oxygen release. Surprisingly, this effect was obtained even when as little as about ten percent (10%) of the total hemoglobin administered to the patient was in the form of hemoglobin solution. As a result of the studies described herein, it is believed that addition of hemoglobin solution in conjunction with stored red blood cells will result in a substantial increase in oxygen release over administration of the same total amount of hemoglobin in the form of freshly isolated red blood cells.
The method and compositions of the present invention can restore oxygen delivery capacity of stored red blood cells more rapidly than may otherwise be possible. The present invention can be particularly useful in the treatment of critically ill, infant, and elderly patients. Furthermore, adding hemoglobin and stored red blood cells according to the method of the present invention will cause increased tissue oxygenation despite the presence of microemboli, because the smaller hemoglobin molecules are able to pass through the obstructions and deliver oxygen. The methods and compositions of the present invention improve the oxygen transport and delivery efficiency of stored red blood cells and can extend the useful storage period of stored red blood cells.